Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein mediating Ca2+-independent homotypic cell–cell adhesion in epithelia. EpCAM is also involved in cell signaling, migration, proliferation, and differentiation. Additionally, EpCAM has oncogenic potential via its capacity to upregulate c-myc, e-fabp, and cyclins A & E. Since EpCAM is expressed exclusively in epithelia and epithelial-derived neoplasms, EpCAM can be used as diagnostic marker for various cancers. It appears to play a role in tumorigenesis and metastasis of carcinomas, so it can also act as a potential prognostic marker and as a potential target for immunotherapeutic strategies. First discovered in 1979, EpCAM was initially described as a dominant surface antigen on human colon carcinoma. Because of its prevalence on many carcinomas, it has been 'discovered' many different times. EpCAM therefore has many aliases the most notable of which include TACSTD1 (tumor-associated calcium signal transducer 1), CD326 (cluster of differentiation 326), and the 17-1A antigen. EpCAM expression is not limited to human colon carcinomas; in fact, EpCAM is expressed in a variety of human epithelial tissues, carcinomas, and progenitor and stem cells. However, EpCAM is not found in non-epithelial cells or cancers of non-epithelial origin. EpCAM is expressed on the basolateral membrane of all simple (especially glandular), pseudo-stratified, and transitional epithelia. In contrast, normal squamous stratified epithelia are negative for EpCAM. The level of expression may differ significantly between the individual tissue types. In the gastrointestinal tract, the gastric epithelium expresses very low levels of EpCAM. Expression levels are substantially higher in small intestine, and in colon EpCAM is probably expressed at the highest levels among all epithelial cell types. EpCAM is frequently upregulated in carcinomas but is not expressed in cancers of non-epithelial origin. In cancer cells, EpCAM is expressed in a dispersed pattern across the cell membrane. However, EpCAM expression in carcinomas is often heterogeneous; some cells in a tumor have more EpCAM than other cells in the same tumor. Squamous carcinomas often express EpCAM whereas normal squamous cells do not express EpCAM. EpCAM expression differs between different types of renal cell carcinomas, and EpCAM expression increases during development of androgen resistance in prostate cancer. All of this points towards the utility of EpCAM as a diagnostic tool for various cancers. Although it is identified as a cell adhesion molecule, EpCAM does not structurally resemble any of the four major families of cell adhesion molecules, namely cadherins, integrins, selectins, and members of the immunoglobulin super-family. EpCAM is a glycosylated, 30- to 40-kDa type I membrane protein. The sequence of the EpCAM molecule predicts the presence of three potential N-linked glycosylation sites. It is composed of 314 amino acids. EpCAM consists of an extracellular domain (242 amino acids) with epidermal growth factor (EGF)- and thyroglobulin repeat-like domains, a single transmembrane domain (23 amino acids), and a short intracellular domain (26 amino acids). The extracellular domain is sometimes referred to as EpEX, and the intracellular domain is sometimes referred to as EpICD.